Increasing complexity in TNFR1 signaling

Abstract

Tumor necrosis factor (TNF) and its receptors, TNF receptor-1 (TNFR1) and TNFR2, have received considerable attention in basic and clinical research for more than two decades. This is because of, on the one hand, the overwhelming importance of TNF-blocking reagents in the treatment of autoimmune diseases and, on the other hand, the fact that practically every cell type responds in some way or another to TNF. The effects of TNF on cells are highly variable and reach from the induction of proliferation or differentiation over the activation of inflammatory processes to cell death. This is mirrored by the fact that TNF stimulates a diverse set of signaling pathways resulting in the activation of apoptotic caspases, inhibitor of jB kinases, MAP3 kinases and sphingomyelinases. It is particularly intriguing that, depending on environmental factors, the same cell-type can respond to TNF with such contrasting effects as cell death and inflammatory cell activation. Research on the signaling pathways ⁄mechanisms mediating these opposing cell fates was therefore in the center of TNF-related research early on, and was formative for the field of cell death and NF-jB research. TNF-related studies, for example, not only resulted in the definition of two novel adapter protein families, the death domain-containing adaptor proteins and the TNF receptor-associated factors (TRAFs), but also led to the identification of the inhibitor of jB kinase complex and a variety of NF-jB regulatory mechanisms. Until a few years ago, the simple picture prevailed that TNFR1-induced apoptosis and necrosis and TNFR1-stimulated activation of NF-jB transcription factors rely on the use of basically linear signaling pathways. Activation of the classical NF-jB pathway by TNFR1 was assigned to the recruitment of receptorinteracting protein-1 (RIP1), TNF receptor-associated death domain (TRADD) and TRAF2, which in a cooperative manner then secondarily recruit and activate the inhibitor of jB kinase complex and thus the classical NF-jB pathway. TNF-induced necrosis was further traced to activation of the kinase activity of RIP1 which, however, is dispensable for NF-jB signaling. TNFR1mediated apoptosis was found to require internalization and sequential action of the TRADD-interacting death domain adapter protein Fas-associated death domain (FADD) and the FADD-interacting protease caspase 8. The balance between these TNFR1-associated pathways and thus the cellular fate in response to TNF was considered to be mainly controlled by pre-existing and NF-jB-induced prosurvival proteins. In recent years, it has turned out that the situation is much more complicated than initially anticipated. Different types of ubiquitylation of several TNF signaling intermediates have been identified not only as pivotal events in TNFR1-mediated NF-jB activation, but also play a crucial role in the control of a novel RIP1-dependent mode of caspase 8 activation. Further, it became evident that most proteins involved in TNF signaling are less obligatory than previously thought, and more than 10 years after their identification as components of the TNFR1 and TNFR2 signaling complexes, the TRAF2-associated proteins cIAP1 and cIAP2 are recognized as important regulators of apoptotic and inflammatory TNFR1 signaling. Moreover, it has been recognized that TNFR2 modulates TNFR1 signaling by regulation of the TNFR1-‘available’ cytoplasmic pool of TRAF2–cIAP complexes. This minireviews series covers these novel and exciting aspects of TNF signaling and tries to address new questions emerging from these developments. The first minireview by Wajant and Scheurich is focused on the mechanisms of TNFR1-induced NF-jB activation and particularly highlights recent details of the regulatory role of nondegrading protein ubiquitylation for this process. The second minireview by O’Donnell and Ting focuses on the role of RIP1 and ubiquitylation in TNFR1-induced cell death. Finally, Naude et al. discuss, in the context of TNFR2, how the aforementioned TNFR1-associated signaling pathways can be modulated by external cues.